The present invention relates to a polarity-inverting type iontophoresis device capable of controlling transdermal or transmucosal drug administration for a long time. In particular, the present invention relates to an iontophoresis device which can effectively maintain safe and stable absorptivity for a long time utilizing electric driving force and which can be produced with a low cost.
Iontophoresis is a transdermal-absorption promotion system using electricity as external stimulation. It is based on a mechanism that across an electric field generated between an anode and a cathode mainly by energization, molecules with a positive charge move from the anode to the cathode while those with a negative charge move from the cathode to the anode, to generate force, which promotes penetration of a drug molecule through the skin barrier (See, Journal of Controlled Release, Vol. 18, 1992, pp. 213-220; Advanced Drug Delivery Review, Vol. 9, 1992, p.119; Pharmaceutical Research Vol. 3, 1986, pp. 318-326).
Iontophoresis generally involves a power supply, a drug reservoir electrode and an electrolyte reservoir electrode. An electrode which may be used in this system may be an active electrode such as a silver or silver chloride electrode or an inactive electrode such as a platinum or titanium electrode. In case of an inactive electrode, hydrogen ions and oxygen gas are generated on an anode side and hydroxyl ions or hydrogen gas are generated during energization on a cathode side. It is well known that hydrogen ions and hydroxyl ions generated by the inactive electrode may induce skin irritation or reduce of a drug delivery rate.
Anode side: 2H2Oxe2x86x924H++O2+4exe2x88x92
Cathode side: 2H2O+2exe2x88x92xe2x86x9220Hxe2x88x92+H2 
On the other hand, in an active electrode, a redox reaction occurs at a lower voltage than that in electrolysis of water. Typical electrode materials include silver and silver chloride. Generally, an anode is made of a silver electrode and an electrolyte reservoir contains a counter material, e.g., chloride ions, required for a redox reaction with the electrode. Thus, metal ions (e.g., silver ions) eluted from the anode electrode react with chloride ions in the reservoir to form an insoluble precipitate (e.g., silver chloride). It can substantially inhibit transfer of the metal ions to the skin so that an active electrode is safer to the skin than an inactive electrode.                     Anode        ⁢                  xe2x80x83                ⁢        side        ⁢                  :                                    Ag        →                              Ag            +                    +                      e            -                                                  xe2x80x83                                                  Ag            +                    +                      Cl            -                          →        AgCl                                Cathode        ⁢                  xe2x80x83                ⁢                  side          :                                              AgCl          +                      e            -                          →                  Ag          +                      Cl            -                              
Use of an active electrode has, however, encountered problems of competition between a cationic drug and counter ion species to chloride ions in an anode side and reduction in absorptivity due to competition between an anionic drug and chloride ions eluted from the electrode in a cathode side. An active electrode itself may be oxidized or reduced. It is, therefore, difficult to maintain performance as an active electrode for a long-term use.
Thus, devices and methods have been recently developed for solving the problem of competitive ions in the above electrode. In particular, there has been improvement in terms of competitive ions eluted from an electrode, which represents a problem in use of an active electrode. As a method for inhibiting such metal-ion transfer in an active electrode, National Publication of the International Patent Application Nos. 3-504813 and 3-504343 have disclosed a device where a material causing an electrode reaction at a lower voltage than that in hydrolysis of water is used as a current distributing member and a charge-selecting material layer is placed between an electrode and a drug reservoir or between the body surface and an electrode. The charge-selecting material contains counter ions reacting with the electrode. National Publication of the International Patent Application No. 5-506158 has disclosed a device comprising a donor electrode, an electrolyte reservoir, a selective permeable membrane and a drug reservoir, where the electrolyte reservoir contains counter ions reacting with the electrode. In these techniques, it has been indicated that counter ions to the counter ions reacting with the electrode have the same polarity as a drug, leading to a reduction in the drug delivery rate and that a chloride bound to a polymer (e.g., quaternary ammonium chloride) may be used to avoid the problem. Such modification, however, mainly aims at effective drug delivery and there have remained problems in terms of practicability and versatility due to its complex structure. There have been disclosed no means for maintaining electrode performance for a long-term use.
Electrode materials which may be used in an active electrode such as silver and silver chloride are generally expensive. Thus, in practical production, incorporating these metal materials (for example, a silver foil) in a device is undesirable in terms of productivity and a production cost. Furthermore, there have been significant problems for developing an iontophoresis device for a long-term use, i.e., problems in terms of maintaining electrode performance for a long time such as life expiration due to electrode deterioration in an active electrode such as a silver or silver chloride electrode, i.e., insulation in an electrode due to precipitation of non-conductive silver chloride on the electrode surface caused by long-term energization in an anode side and life expiration as an active electrode due to elution of chlorine from silver chloride during energization in a cathode side.
On the other hand, there have been developed electrodes improved for long-term use. Japanese Patent Laid-Open Publication No. 9-276416has disclosed an electrode comprising a main electrode consisting of an active electrode and a regeneration electrode as an inactive electrode. Japanese Patent Laid-Open Publication No. 4-312471 has disclosed a device which can be used for a long time using a removable electrolyte reservoir in a housing comprising an inactive electrode. This publication has, however, disclosed regeneration or reuse of an electrode itself in the device using an active electrode and has not consider effects on drug absorptivity induced by competing ions generated during energization and an electrolyte added so that absorption cannot be strictly controlled.
Furthermore, there have been developed devices using a polarity inverting apparatus. For inhibiting generation of harmful hydrogen or hydroxyl ions in an inactive electrode, adjustment of pH by switching polarity is disclosed in Japanese Patent Publication No.60-34396 in which a ratio of a positive current energy amount to a negative current energy amount is within a range of about 2:1 to 7:1 and in EP 0776676 using 0.0027 Hz to 10 Hz. Japanese Patent Laid-Open Publication No. 4-224770 has disclosed that a sign of voltage applied between electrodes is inverted to adjust pH. In such a device, an inactive electrode which is not deteriorated is used and polarity is inverted during energization to inhibit pH variation for improvement in skin irritation. The technique does not improve the problem of generation of gases such as oxygen and hydrogen so that when it is used for a long period, a gas may fill the device and a special structure such as a vent hole is necessary. There has not been thus solved the problem of difficulty in producing an electrode comprising such an element.
In addition, U.S. Pat. No. 4,406,658 has disclosed that a device by which polarity of an electrode can be inverted comprises means for inverting polarity of an electrode to conduct iontophoresis in both electrodes with one application. National Publication of the International Patent Application No. 9-503136 has described that polarity may be inverted to reduce irritation during energization. In the above prior art, no device has been described, which provides safe and stable absorption for a long period, rather than a polarity inverting device for long-term drug delivery.
On the other hands, many diseases require sustained drug delivery for a long period. A patient with such a disease has been substantially treated by invasive procedures such as infusion. Treatment with infusion, however, not only requires hospitalization but also more imposes a burden on a patient. For overcoming such disadvantages, some formulations such as a sustained formulation and an implant have been investigated, but there is limitation of such a formulation in strictly controlling a blood level. Furthermore, when a serious side reaction occurs, drug administration cannot be discontinued. Iontophoresis has been also paid attention as a new drug delivery system in place of an injection as an administration system for a drug requiring strict administration control. If an iontophoresis formulation by which absorption to the same level as that in an injection may be achieved and which allows a patient to administer a drug by him/herself is developed, home treatment may be realized. Precise control of an energization time may allow a given absorption pattern to be achieved. In particular, it may lead to more effective drug treatment for a drug requiring administration control.
An object of the present invention is to provide an iontophoresis device whereby effective and continuous absorption may be maintained for a long period. Another object of the present invention is to provide a long-term type iontophoresis device with higher safety, versatility and practicability which can maintain electrificity and absorpability without reducing a drug delivery rate which provide high bioavailability of a drug the present invention may be generally applicable to the skin, but also applicable to the mucosa.
The inventors have intensely attempted for achieving the above objects and have finally found that two electrode structures (first and second electrode structures) comprising an electrode member consisting of a mixture containing silver and silver chloride contain given amounts of chloride ions and of an active ingredient and energization is conducted using a power supply equipped with polarity inverting means to achieve safe, effective and continuous absorption for a long period. After further investigation, we have also found that irrespective to polarity of a drug, in this device, a chloride-ion content may be selected depending on a time of polarity-inverting for inhibiting transfer of competing ions, to allow the drug to be transdermally administered with a higher bioavailability and good reproductivity. The present invention discloses a chloride-ion content in an electrode structure comprising an active electrode, a substance for supplying chloride ions and an optimal device, in order to allow safe energization for a long period time without causing a reduction of absorption efficiency by means of an energization method using polarity inverting means. It may provide a safe and inexpensive polarity-inverting type iontophoresis device which can strictly control drug administration for a long period.
In particular, for polarity at initial energization, when the first and the second electrode structures are an anode side and an cathode side, respectively, chloride ions in the first electrode structure react with silver ions in the electrode in the anode side, while in the cathode side, silver chloride in the electrode member is oxidized, resulting in elution of chloride ions into the second electrode structure.
Initial electrode reaction in the first electrode structure: Ag++Clxe2x88x92xe2x86x92AgCl
Initial electrode reaction in the second electrode structure: AgCl+exe2x88x92xe2x86x92Ag+Clxe2x88x92
After polarity inversion, in the anode side, silver chloride precipitated on the electrode surface in the initial electrode reaction is oxidized and chloride ions are eluted into the first electrode structure. In the cathode side, chloride ions eluted into the second electrode structure in the initial electrode reaction react with silver ions in the electrode member.
Initial electrode reaction in the first electrode structure: AgCl +exe2x88x92xe2x86x92Ag+Clxe2x88x92
Initial electrode reaction in the second electrode structure: Ag++Clxe2x88x92xe2x86x92AgCl
These electrode reactions may be utilized to optimize the chloride-ion content in the first electrode structure and a polarity inverting time and thus energization can be maintained for a long period. On the other hand, when polarity is inverted after energization to a certain direction, chloride ions in the anode side which subsequently react with the electrode are limited to those which have been eluted from the electrode. Thus, the amount of chloride ions which can react with the electrode is limited. A polarity inverting time must be, therefore, strictly controlled. When an irreversible reaction occurs between anions extracted from the skin in the anode side and silver ions eluted from the electrode, the content of silver in the electrode plays an important role in long-term energization. It means that the contents of silver and silver chloride in the electrode must be adjusted, depending on an energization time and a polarity inverting time.
A preferred embodiment for avoiding these problems is, therefore, a device comprising two electrode structures containing a given amount of chloride ions and at least one active ingredient; an active electrode in each electrode structure, which is made of a mixture containing at least silver and silver chloride; and a power supply equipped with polarity inverting means which is electrically connected to an electrode member in each electrode structure for altering a current direction between two electrode structures. In this type of device, even when an irreversible reaction occurs between anions extracted from the skin and silver ions in the electrode in the anode side or a small deviation occurs in a polarity inverting time, there are no effects during a long-term energization because there are, as silver chloride, chloride ions more than those reacted corresponding to a polarity inverting time in any electrode member and each electrode structure contains chloride ions.
Specifically, an iontophoresis device according to the present invention comprises the first and the second electrode structures comprising a hydrophilic conductive layer containing at least one active ingredient and an electrode member made of an active electrode material, respectively; and a power supply equipped with polarity inverting means which is electrically connected to the electrode members in the first and the second electrode structures between them for altering a current direction between the two electrode structures, wherein at least one of the first and the second electrode structures contains chloride ions and before administration, a chloride-ion content (P mg) is within a range satisfying equation (1):
1.0xc3x97(Ixc3x97Txc3x970.022)xe2x89xa6P xe2x80x83xe2x80x83. . . (1) 
wherein T represents a polarity inverting time (min) until polarity is inverted after energization in a certain direction and I represents an average current (mA).
The active ingredient is neutral or cationic and polarity inversion is periodically repeated by the power supply.
Alternatively, an iontophoresis device according to the present invention comprises the first and the second electrode structures comprising a hydrophilic conductive layer containing at least one active ingredient and an electrode member made of an active electrode material, respectively; and a power supply equipped with polarity inverting means which is electrically connected to the electrode members in the first and the second electrode structures between them for altering a current direction between two electrode structures, wherein at least one of the first and the second electrode structures contains chloride ions and before administration, a chloride-ion content (P mg) is within a range satisfying equation (2):
1.0xc3x97(Ixc3x97Txc3x970.022)xe2x89xa6Pxe2x89xa6100xc3x97(Ixc3x97Txc3x970.022) xe2x80x83xe2x80x83. . . (2) 
wherein T represents a polarity inverting time (min) until polarity is inverted after energization in a certain direction and I represents an average current (mA).
The active ingredient is anionic and polarity inversion is periodically repeated by the power supply.
The power supply comprises timer means for controlling a polarity inverting time. The above chloride ions are contained in the above hydrophilic conductive layer or an additional hydrophilic conductive layer placed between the electrode member and the hydrophilic conductive layer.
The first and the second electrode structures may have the same composition comprising a given amount of chloride ions and at least one active ingredient.
The electrode member is formed by printing a conductive ink containing at least silver and silver chloride. A composition ratio or mixing ratio of silver and silver chloride in the electrode member is preferably 1:9 to9:1. The electrode member may further contain a halogenated compound.
The above chloride ions may be supplied from hydrochloric acid. Alternatively, the chloride ions may be supplied from at least hydrochloride of an active ingredient or from at least a resin or polymer containing quaternary ammonium chloride. The resin may be selected from the group consisting of ethyl acrylate-methyl methacrylate-ethyl methacrylate trimethylammonium chloride copolymers and cholestyramine.
The electrode structures contain an organic amine as a pH adjusting material. A pH adjusting material is, for example, at least one of meglumine, tromethamol, triethanolamine and aminoacrylate. The power supply may comprise means for shorting a circuit in polarity inversion and/or means for providing a non-energization time for a given period. Polarity inversion by the power supply is conducted at least once, where a time for one polarity inversion is preferably 1 min to 2 hours. Current applied by the power supply is at least one of direct current, pulse direct current and pulse depolarized direct current.
The electrode structures comprise an insulating support in which a pit, which accommodates the electrode member and the hydrophilic conductive layer and whose surface may be covered by a semipermeable membrane, a selective permeation membrane, a control membrane or a hydrophilic porous membrane.